Heart failure (HF) is accounts for 1 in 9 deaths in the United States and currently affects ~6 million with a prevalence of 250,00-400,000 and incidence of 70,000-120,000. Current therapy does not address the underlying loss of functional heart muscle and adverse structural remodeling. One novel potential treatment of HF is exercise (aerobic) therapy that has demonstrated various cardioprotective properties to halt and potentially reverse adverse structural remodeling. However, dosing of exercise therapy remains a challenge due to each individual's inherent differences and consequentially, serial non-invasive monitoring of the therapy would be necessary to evaluate the change on structural remodeling. Furthermore, current non-invasive technologies characterize structural remodeling with surrogate measures and thus, there is no consensus on a single clinical gold-standard. Without a tool to monitor and characterize the degree of structural remodeling, the evaluation of the therapeutic potential of exercise therapy in HF patients cannot be fully realized representing an unmet need in ultimately improving therapy. The proposed project aims to improve the therapy monitoring of exercise training to cardioprotect against HF by revealing its effect on microstructural remodeling with cardiac diffusion tensor MRI (DT-MRI). DT-MRI is a unique, non-invasive technology capable of characterizing myocardial fiber orientation and directly reflecting microstructural remodeling. However, despite major advances, there are fundamental challenges that limit the capability of current cardiac DT-MRI methods to be applied robustly in a clinical setting. In this project, an innovative 5-min ?push button? DT-MRI method will be developed that overcomes such limitations. We also leverage institutional strengths to further quantify the accuracy of in vivo DT-MRI in revealing myocardial microstructure using novel tissue cleared 3D histology. The central hypothesis is that addressing these major technical challenges will allow for clinical translation of cardiac DT-MRI to serve as a tool to monitor the therapeutic effects of HF on microstructural remodeling. This is achieved by extending previously developed technologies used for myocardial fibrosis detection with diffusion-weighted MRI. The proposed project is designed to systematically develop an innovative and robust clinical DT-MRI methodology and rigorously validate in a pre-clinical setting the effects of exercise therapy on the microstructural remodeling of HF thereby laying the groundwork for potential optimization of dosing exercise therapy.